Basigin is a member of the immunoglobulin (Ig) superfamily, with a structure related to the putative primordial form of the family. As members of the immunoglobulin superfamily play fundamental roles in intercellular recognition involved in various immunologic phenomena, differentiation, and development, basigin is thought also to play a role in intercellular recognition (Miyauchi et al., 1991; Kanekura et al., 1991).

By screening an expression library of a mouse embryonic carcinoma cell line, Miyauchi et al. (1990) obtained a cDNA encoding an Ig superfamily protein that they termed basigin, for 'basic immunoglobulin.' Miyauchi et al. (1991) identified the homologous human sequence by probing a human gastric carcinoma cell line with the mouse cDNA probe. The deduced 269-amino acid human protein contains a 22-amino acid signal sequence, an extracellular domain with 3 potential N-glycosylation sites, a 24-amino acid transmembrane domain, and a cytoplasmic region. Human basigin shares 58% and 28% amino acid identity with mouse basigin and embigin (EMB; 615669), respectively. It also shares significant homology with human MCH class II beta chain. Northern blot analysis detected a 2.0-kb transcript in the gastric carcinoma cell line.

Kanekura et al. (1991) showed that different forms of basigin could be produced in mouse via different modes of glycosylation. They also identified cDNA clones with different 5-prime coding sequences, suggesting possible variation in the N-terminal sequence of basigin.

By biochemical, immunochemical, and micropeptide sequencing analyses, Spring et al. (1997) determined that the OK blood group antigen (see 111380) is identical to the M6 leukocyte activation antigen and BSG. Flow cytometric analysis demonstrated ubiquitous expression in leukocytes. Immunohistochemistry indicated that OK antigen is expressed in a number of normal human tissues as well as in malignant cells. Immunoblot analysis showed expression of a 34-kD protein and a 50- to 70-kD protein of similar size to that seen in erythrocyte membranes.

By PCR using primers designed from purified peptide fragments, followed by RACE, Biswas et al. (1995) cloned EMMPRIN. The deduced 269-amino acid protein encodes a 21-amino acid N-terminal signal peptide, followed by a 185-amino acid extracellular domain, a putative transmembrane region, and a short C-terminal domain. The extracellular domain contains 2 immunoglobulin-like subdomains, and the putative transmembrane region has features of a leucine zipper motif. Northern blot analysis detected a 1.7-kb EMMPRIN transcript in a human hepatic stellate cell line.

Wu et al. (2011) stated that there are 4 splice variants of BSG. RT-PCR showed that only variant-2 was expressed in peripheral blood mononuclear cells. Variant-2 lacks exon 3 and encodes a protein with a deletion in its N-terminal region compared with the full-length protein.

Guo et al. (1998) determined that the BSG gene contains 8 exons and spans 10.8 kb. Exon 1 contains the 5-prime UTR and the translation start site, which falls within a CpG island. The 5-prime flanking sequence contains 3 consensus binding sites for SP1 (189906) and 2 sites for AP2 (107580), but no TATA or CAAT boxes.

Wu et al. (2011) reported that the BSG gene contains 10 exons. The first 4 exons, including 2 alternative first exons, are subject to alternative splicing.

Kaname et al. (1993) mapped the human BSG gene to chromosome 19p13.3 by fluorescence in situ hybridization. Using an interspecific backcross panel and microsatellite polymorphisms as markers, Simon-Chazottes et al. (1992) mapped the gene for basigin (Bsg) to mouse chromosome 10.

Pushkarsky et al. (2001) identified CD147 as a receptor for extracellular cyclophilin A (CYPA; 123840). They found that CD147 enhanced human immunodeficiency virus (HIV)-1 infection through interaction with CYPA incorporated into virions. Virus-associated CYPA coimmunoprecipitated with CD147 from infected cells, and antibody to CD147 inhibited HIV-1 entry. Viruses whose replication did not require CYPA were resistant to the inhibitory effect of anti-CD147 antibody. Pushkarsky et al. (2001) concluded that HIV-1 entry depends on an interaction between virus-associated CYPA and CD147 on a target cell.

Yurchenko et al. (2001) determined that CD147 also serves as a receptor for cyclophilin B (CYPB; 123841). CYPB induced Ca(2+) flux, ERK (see MAPK3; 601795) phosphorylation, and chemotaxis in CD147-transfected Chinese hamster ovary cells, but not in control cells. The chemotactic response of primary human neutrophils to CYPB was blocked by antibodies to CD147.

Using expression cloning, Renno et al. (2002) identified CD147 as a molecule expressed on the surface of cycling thymocytes. CD147 expression correlated with immature thymocyte cycling, and ligation of the molecule on these cells inhibited their development into mature T cells.

Zhou et al. (2005) identified CD147 as a subunit of native gamma-secretase complexes (see PSEN1; 104311) purified from HeLa cell membranes. Coimmunoprecipitation studies confirmed the presence of CD147 in HeLa cell complexes and in soluble complexes from a human neural cell line and embryonic kidney cells. Depletion of CD147 by RNA interference increased production of amyloid-beta (see APP; 104760) peptides without changing the expression of other gamma-secretase components or APP substrates. Zhou et al. (2005) concluded that the presence of CD147 within the gamma-secretase complex downmodulates production of amyloid-beta peptides.

Schreiner et al. (2007) found that SHREW1 (AJAP1; 610972), a protein associated with cellular invasion, interacted with CD147 in epithelial cells. Downregulation of SHREW1 or CD147 using small interfering RNA in HeLa cells decreased invasiveness without affecting proliferation. Schreiner et al. (2007) concluded that SHREW1-CD147 interaction is associated with regulation of cellular invasion.

By systematic screening of a library of erythrocyte proteins, Crosnier et al. (2011) identified basigin as a receptor for PfRh5, a Plasmodium falciparum ligand essential for blood stage growth of the parasite, the causative agent of malaria (see 611162). Soluble basigin or basigin knockdown inhibited erythrocyte invasion by all P. falciparum strains, and complete blocking was achieved by anti-basigin antibodies. OK(a-) red blood cells, which express the glu92-to-lys (E92K; 109480.0001) variant of basigin, had reduced binding to PfRh5 due to slower association and faster dissociation rates. Another basigin variant, leu90 to pro (L90P), did not interact with PfRh5 at all. Crosnier et al. (2011) concluded that the dependence on a single receptor-ligand pair across many P. falciparum strains may provide novel possibilities for therapeutic intervention.

Using immunohistochemistry in mouse testis, Mannowetz et al. (2012) showed that Bsg was expressed in elongating spermatid cytoplasm and sperm tails, whereas Emb (615669) localized in sperm tails only. Mct1 (600682) was detectable in spermatozoa tails and plasma membranes of both spermatocytes and spermatids, whereas Mct2 (603654) was present in sperm tails and cytoplasm of Sertoli cells. The distribution of Bsg, Emb, Mct1, and Mct2 differed in epididymis and epididymal sperm. Bsg colocalized with Mct1 and Mct2 in spermatozoa, but Emb did not colocalize and was detected in the principal piece and the acrosome. Immunoblot analysis showed that in epididymal sperm, Bsg was expressed as a 51-kD proteolyzed protein, Emb as a 40-kD protein, Mct1 as a 40- to 48-kD protein, and Mct2 as a 40-kD protein. Mct1 and Mct2 coimmunoprecipitated with Bsg, but not Emb, in cauda sperm preparations. Functional analysis showed that Mct1 and Mct2 were active and provided the cells with L-lactate. Mannowetz et al. (2012) proposed that BSG interacts with MCT1 and MCT2 to locate them properly in the membrane of spermatogenic cells and that this may enable sperm to use lactate as an energy substrate.

The integration of endocytic routes is critical to regulate receptor signaling. A nonclathrin endocytic (NCE) pathway of the epidermal growth factor receptor (EGFR; 131550) is activated at high ligand concentrations and targets receptors to degradation, attenuating signaling. Caldieri et al. (2017) performed an unbiased molecular characterization of EGFR-NCE and identified NCE-specific regulators, including the endoplasmic reticulum (ER)-resident protein reticulon-3 (RTN3; 604249) and a specific cargo, CD147. RTN3 was critical for EGFR/CD147-NCE, promoting the creation of plasma membrane (PM)-ER contact sites that were required for the formation and/or maturation of NCE invaginations. Ca(2+) release at these sites, triggered by inositol 1,4,5-trisphosphate (IP3)-dependent activation of ER Ca(2+) channels, was needed for the completion of EGFR internalization. The authors concluded that they identified a mechanism of EGFR endocytosis that relies on ER-PM contact sites and local Ca(2+) signaling.

Wu et al. (2011) noted that a psoriasis susceptibility locus, PSORS6 (605364), is located on chromosome 19p13, where the BSG gene maps. They genotyped a T-to-A SNP, rs8259, in the 3-prime UTR of the BSG gene in 668 psoriasis patients and 1,143 healthy controls from a central south Chinese population. The T allele was associated with significantly decreased susceptibility to psoriasis (odds ratio = 0.758; p = 0.002). Wu et al. (2011) found that the T allele of rs8259 created a functional binding site for microRNA-492 (MIR492; 614384), leading to reduced translation of the BSG transcript. In contrast, the A allele abolished the MIR492-binding site and was associated with increased expression of BSG variant-2 in peripheral blood mononuclear cells.

Plasmodium falciparum (Pf) (see 611162) belongs to the Laverania subgenus of malaria parasites. Other members of the subgenus infect African apes but not humans, and Pf does not infect wild chimpanzees or gorillas. Using recombinant proteins and biophysical assays, Wanaguru et al. (2013) showed that EBA175 from ape Laverania bound to human erythrocyte GYPA (617922) with an affinity similar to that of Pf. However, PfRh5, which interacted with human erythrocyte BSG with high affinity, bound with 10-fold lower affinity to chimpanzee Bsg and did not bind at all to gorilla Bsg. Mutation analysis indicated that lys191 in the second Ig domain of human BSG was critical for PfRh5 binding. This residue is glu in chimp Bsg, explaining its reduced affinity for PfRh5, but gorilla Bsg also contains lys191. However, gorilla Bsg contains a his103 insertion and 2 other changes, phe27 to leu and gln100 to lys, in the first Ig-like domain that are absent in human and chimpanzee BSG, and these changes appeared to play a role in the inability of gorilla Bsg to bind PfRh5. Wanaguru et al. (2013) concluded that species-specific differences in the interaction of PfRh5 with ape BSG orthologs are a plausible explanation for the absence of Pf in wild ape populations.

Naruhashi et al. (1997) generated mice deficient in basigin by targeted disruption. Bsg -/- mice showed worse performance than their wildtype and heterozygous littermates in the Y-maze task, which assesses short-term memory, and in the water-finding task, which examines latent learning, without any motor dysfunction. Moreover, the mutant mice showed less acclimation in the habituation task compared with the wildtype mice. The mutant mice were also more sensitive to electric foot shock. Naruhashi et al. (1997) found these findings consistent with the expression profile of basigin in the central nervous system and suggested that basigin may play an important role in learning and memory as well as in sensory functions.

Kuno et al. (1998) demonstrated that female mice deficient in basigin are infertile due to failure of female reproductive processes including not only implantation but also fertilization. Bsg mRNA expression in cumulus cells and basolateral localization of the Bsg protein in the endometrial epithelium further support the importance of Bsg in these processes.

In Bsg -/- mice, Philp et al. (2003) found severe reduction in accumulation of MCT1 (600682) and MCT3 (610409) proteins in the retinal pigment epithelium and concomitant reduction in the MCT1 and MCT4 (603877) proteins in the neural retina, supporting a role for basigin in the targeting of these transporters to the plasma membrane. The authors concluded that decreased expression of MCT1 and MCT4 on the surfaces of Muller and photoreceptor cells might compromise energy metabolism in the outer retina, leading to abnormal photoreceptor cell function and degeneration.

In order to determine the contribution of genetic background on the Bsg-null phenotype, Chen et al. (2004) developed 3 strains of Bsg-null mice. In 2 strains, lack of Bsg caused a high rate of embryonic lethality, sterility in both sexes, and blindness associated with abnormal electroretinograms and retinal degeneration predominantly in the photoreceptor layer. The third strain showed higher embryonic survival, but infertility and blindness persisted.